Viruses such as measles, influenza, and HIV cause considerable morbidity worldwide. New emerging viruses are a constant threat because of the speed of their spread and their potential to cause widespread disease before therapies can be developed. Not much is known about innate immune responses against viruses. The immune signaling pathways in Drosophila are highly conserved with immune pathways in humans, worms, and plants, making it an excellent model for study. We have established a system to examine antiviral innate immune responses using the dsRNA birnavirus, Drosophila X virus (DXV) infection of Drosophila melanogaster. We have identified the Toll and RNAi pathways as important for host defense. From a forward genetic screen, we have also identified novel mutations important for viral pathogenesis or the antiviral immune response. The specific aims of this proposal are: 1. To determine whether the new DXV-susceptible mutants are acting in the Toll, RNAi, or JAK/STAT pathways. 2. To study how an overactive immune response can be damaging to the host. An overactive immune response appears to be harmful to the fly during DXV infection. We will determine the possible role of the Toll pathway in this response and characterize the DXV-resistant mutants to potentially identify negative regulators of this pathway. 3. To identify by map-based positional cloning two novel antiviral genes that affect either the Toll or RNAi pathway. Overall, the proposed experiments may give insight to new pathways, or new genes in Toll or RNAi pathways that are important for antiviral immune responses. PUBLIC HEALTH RELEVANCE Viruses come in many varieties and are successful in causing disease in humans;the Toll pathway and RNA interference (RNAi) are two means that the host uses to combat viral infection. We will identify novel genes important for the antiviral immune response and determine if they are affecting these two pathways.